Cyclopentene sulfoxides

ABSTRACT

The novel synthesis of chemical compounds of the structures 1 and 2 is disclosed. ##STR1## wherein R 1  is a member of the group consisting of alkyl, (cis or trans) alkenyl and alkynyl groups of from 2 to 9 carbon atoms which can be substituted by a terminal 1,3-dioxyacyclopentyl, a carboxyl or a carboalkoxy (--COOR&#39;) group where R&#39; is an alkyl group of 1 to 6 carbon atoms. Compounds 1 and 2 are shown to be useful intermediates in prostaglandin synthesis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of copending application Ser. No.499,287, filed Aug. 21, 1974, now abandoned, which is acontinuation-in-part of copending application Ser. No. 349,888, filedApr. 10, 1973, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to the synthesis of compounds of formula 1 whichare known to be useful for a variety of purposes including use asintermediates in the synthesis of prostaglandins. In the above formula,R₁, defined below, includes a member of the group consisting of alkyl,alkenyl, and alkynyl groups of from 2 to 9 carbon atoms which can besubstituted by a terminal carboxyl or carboalkoxy group (-COOR') inwhich the alkyl group (R') is from 1 to 6 carbon atoms.

In J. Am. Chem. Soc. 95:5, Mar. 7, 1973, pp 1676-7 there is described asynthesis of prostaglandin E₁ in which2(6-carboethoxyhexyl)-4-(2-hydroxy)-2-cyclopentne-1-one (i.e., formula 2where R₁ is 6-carboethoxyhexyl group) is used as an intermediate.

STATEMENT OF THE INVENTION

The first section of this invention relates to the stereo-selectivesynthesis of 1-substituted 1-cyclopentene-cis-3,5-diols (1) where R₁ inthe formula includes a member of the group consisting of alkyl, alkenyland alkynyl groups of from 2 to 9 carbon atoms which can be substitutedby a terminal 1,3-dioxacycyclopentyl, a carboxyl, or a carboalkoxy group(-COOR') in which the alkyl group (R') is from 1 to 6 carbon atoms.

The compounds of general structure 1 can be prepared from the hydroxysulfoxides 6 and 7 in which R is a hydrocarbon radical of from 1 to 12carbon atoms such as butyl, hexyl, decyl, phenyl or methyl, or anitrogen and/or sulfur containing 5 ot 6 membered heterocyclic radicalsuch as 2-pyridyl, 2-thiazolinyl or 1-alkyl-2-imidazolyl. ##STR2##

A general synthetic approach to 6 and 7 is described below for R =phenyl, i.e. Ph. it will be understood that the values for R given canbe used in the scheme. ##STR3##

The processes above are thus a method of producing a compound of theformula ##STR4## which comprises reacting a compound of the formula:##STR5## with an alkyllithium and then with RSHal wherein R is ahydrocarbon radical of from 1 to 12 carbon atoms or a nitrogen and/orsulfur containing 5 or 6 membered heterocyclic radical, Hal is ahalogen; and allowing the resulting sulfenate ester of the formula:##STR6## to rearrange, and also a method of producing a compound of theformula: ##STR7## which comprises reacting a compound of the formula:##STR8## with RSH in the presence of an organic base wherein R is thesame as described immediately above to produce a compound of theformula: ##STR9## and reacting the latter with a peracid to givecompounds of the general structure 7. Both compounds 6 and 7 exists as adiastereoisomeric mixture at the sulfur atom.

EXPERIMENTAL

Both 6 and 7 were prepared as a mixture of sulfoxide diastereoisomers atsulfur. The steroochemical assignments are based on the mode ofsynthesis.

The cis isomer 6 was prepared by treatment of a 0.25 molar solution of 8in dry tetrahydrofuran (THF) with one equivalent of n-butyllithium(hexane) at -60° followed by titration with phenylsulfenyl chloride(about 1.25 equivalent) until the persistence of a yellow color. Theresulting sulfenate ester 9 was allowed to rearrange to the cis-hydroxysulfoxide 6 by standing at -20° to +5° C over a 1.5-hour period. Thecrystalline product 6 was isolated by ether extraction of the aqueousreaction mixture. Sublimation of the product (95°, 0.05 mm Hg) afforded6, m.p. 102°-112° C, (diastereoisomeric at sulfur) in 55-70% yield, nmr(CDCl₃) δ; 7.51 (m, 5H), 6.20 (m, 1H), 5.20 (m, 1H), 3.90 (d, 1H), 3.80(m, 1H), 2.66 (m, 2H); in (CDCl₃), cm⁻¹ ; 3375, 3040, 1090, 1040, massspectrum (70 ev) m/e 208 m+.

Anal. Calcd for C₁₁ H₁₂ O₂ S: C, 63.45; H, 5.81. Found: C, 63.43; H,5.86.

The synthesis of the trans-hydroxy sulfoxide 7 (R=Ph) was accomplishedin two steps in an overall yield of 91% starting from epoxycyclopentene(10) following the method of M. Korach et al., Org. Syntheses, 42 50(1962). Treatment of a 2.5 molar solution of 10 in dry benzene at 0°with one equivalent each of thiophenol and triethylamine followed bystirring at 25° C for 4 hours afforded exclusively the trans-hydroxysulfide as a homogenous liquid (molecular distillation; 90°, 0.05 mm Hg)in 96% yield; nmr (CDCl₃) δ; 7.3 (m, 5H), 5.8 (m, 2H), 4.4 (m, 1H), 4.1(m, 1H), 2.5 (m, 3H); ir (neat) cm⁻¹ ; 3400, 3100, 2950, 1590.

Anal. Calcd for C₁₁ H₁₂ OS: C, 68.74; H, 6.29. Found: C, 68.82; H, 6.34.

Under the same conditions the trans hydroxy sulfide, 12, can be preparedin 77% yield, bp (molecular distillation 80° at 0.005 mm) m.p. 63°-66°,ir (neat) cm⁻¹ ; 3300, 1460, 1280, 740; nmr (CDCl₃) δ; 6.9 (m, 2H), 6.3(m, 1H), S.9 (m, 1H), 5.6 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.6 (s,3H), 2.6 (m, 2H); mass spectrum (70 ev) m/e 196 (m⁺).

Anal. Calcd for C₉ H₁₂ N₂ OS: C, 55.09; H, 6.16. Found: C, 54.99; H,6.06.

The trans hydroxy sulfide 11 (R=Ph) or 12 can also be prepared accordingto the following general procedure without isolation of thecyclopentadiene epoxide 11.

To a rapidly stirred suspension of 13.25 g (0.125 mol) of anhydroussodium carbonate in 60 ml. of dry benzene is added 8.3 ml. (0.100 mol)of cyclopentadiene. The solution is cooled to 20° C and 8.4 ml. (0.050mol) of commercial 40% peracetic acid solution (FMC Corporation)(previously treated with 0.250 g. of sodium acetate to remove sulfuricacid) is added dropwise over a period of 20 min., maintaining thetemperature at 20° ± 5° C. The solution is allowed to warm to roomtemperature and stirred for 3.5 hr.

The solution is filtered with a Schlenck apparatus under a nitrogenatmosphere and the precipitate washed with 100 ml. of benzene. Thebenzene solution is cooled with an ice bath and 5.1 ml. (0.05 mol) ofthiophenol and 7.0 ml. (0.05 mol) of triethylamine are added rapidly viasyringe. The solution is warmed to room temperature and stirred for 18hours. The solution is extracted with two 50 ml. portions of 5% aqueoussodium hydroxide solution, once with 50 ml. brine and dried withanhydrous granular sodium sulfate. Removal of solvent in vacuo gave 6.1g. (0.032 mol, 64%) of the sulfide as a light yellow oil. The productwas homogeneous by tlc and glpc and was identical in all respects to thematerial prepared directly from 3,4-epoxy-cyclopentene. The aboveobserved regiospecific cleavage of epoxide 10 with a variety of othermercaptide nucleophiles is general.

Oxidation of 11 to the trans-hydroxy sulfoxide 7 was carried out withMCPBA, i.e., m-chloroperbenzoic acid (CH₂ Cl₂, 0° C) in 95% yield.Sublimation (90° C, 10⁻⁵ mm Hg) afforded a nicely crystalline solid,m.p. 96-113°;

nmr (CDCl₃) δ; 7.50 (m, 5H), 6.00 (m, 1H), 5.25 (m, 1H) 4.85 (m, 1H),3.83 (m, 2H), 2.55 (m, 2H); ir (CHCl₃), cm⁻¹ 3350, 3075, 3000, 2925,1580.

Anal. Calcd for C₁₁ H₁₂ O₂ S: C, 63.45; H, 5.81. Found: C, 63.31; H,5.81.

Because both 6 and 7 are hygroscopic: care must be used in handlingthese compounds in subsequent experiments requiring anhydrousconditions.

Compounds 6 and 7 can be resolved into their optical isomers by one oftwo procedures. When R is a nitrogen heterocycle such as 12, standardtechniques can be employed for the resolution of amines via the use ofchiral organic acids such as camphor sulfonic acid. When R is a chiral##STR10## moiety such as menthyl the diastereoisomeric sulfides 6 and 7can be separated by column chromatography.

The following general procedure is applicable for the transformation of6 or 7 to the substituted cis-ciols 1.

The method is one of producing a cis-diol compound ##STR11## wherein R₁is a member of the group consisting of alkyl, (cis or trans) alkenyl andalkynyl groups of from 2 to 9 carbon atoms which can be substituted by aterminal 1,3-dioxyacyclopentyl, a carboxyl or a carboalkoxy (--COOR¹)group where R' is an alkyl group of 1 to 6 carbon atoms, which comprisesreacting a member of the group consisting of compounds of one of thefollowing formulas or mixtures thereof: ##STR12## where R is ahydrocarbon radical of from 1 to 12 carbon atoms, or a nitrogen ornitrogen and sulfur containing heterocyclic radical of 5 or 6 members,with lithium dialkyl amine and hexamethylphosphoramide, allowing thereaction to proceed and thereafter adding R₁ Z wherein Z is a halogenand recovering said cis diol compound from the reaction mixture.

EXAMPLE 2-(3-methyl-2-butenyl)-cyclopent-2-ene-cis-1, 4-diol

To a solution of 1.06 ml. (10.2 mmol) of diethylamine in 15 ml. of drytetrahydrofuran (THF) at -60° was added 3.7 ml. (9.4 mmol) ofn-butyllithium. The solution was stirred at -10° for 15 min. and thencooled to -40°. A solution of 0.816 g. (3.92 mmol) of trans2-phenylsulfinyl-cyclopent-3-ene-1-ol in 30 ml. of THF was added to thissolution, maintaining the temperature at -40°. The resulting orangesolution was stirred at -40° for 30 min., cooled to -60° and 0.60 ml.(5.09 mmol) of 1-bromo-3-methyl-2-butene was added. The solution wasstirred at -40° for 10 min. and the reaction quenched with 2 ml. ofsaturated ammonium chloride solution and 2 ml. of diethylamine. Thesolution was allowed to warm to room temperature over 1 hr. and stirred1.5 hr. at room temperature. The solution was diluted with 200 ml. ofdiethyl ether and extracted 2X with 50 ml. portions of H₂ O and oncewith 50 ml. of brine. The ether phase was dried with anhydrous sodiumsulfate and the solvent removed in vacuo to yield 1.345 g. of brown oil,Chromatography on 90 g. of activity III neutral alumina afforded 470 mg.(2.79 mmol, 71%) of product as a light yellow oil upon elution with 2%methanol in chloroform.

Molecular distillation at 50°, 10⁻⁵ mmHg gave an analytical sample: ir(neat) cm⁻¹ 3350, 3000, 2925, 1660, 1460, 1090, 1060, 860; nmr (CDCl₃) δ5.6 (M, 1H), 5.25 (M, 1H), 4.5 (M, 2H), 4.1 (M, 2H), 2.8 (M, 3H), 1.7(M, 7H).

Anal. Calcd for C₁₀ H₁₆ O₂ : C, 71.39; H, 9.59. Found: C, 71.31; H,9.61.

The following procedure, generally applicable to the abovetransformation was used to synthesize additional typical representativespecies of 1.

To a cooled (e.g. -40° to -60°) solution of 3.3 mmol of lithiumdiethylamide (from butyllithium and diethylamine) in 10 ml. of dry THFunder nitrogen there is added 1-1.5 ml. of dry hexamethylphosphoramidefollowed by 1.5 mmol of 6 or 7 in about 4 ml. of THF, with stirring. Thedeep red solution is stirred for 30 minutes at which time the alkylhalide, R₁ --Z, (1.6 mmol) is added either as a neat liquor or in aminimum volume of THF. Stirring is continued for an additional 30minutes at -40°, and 2 ml. of a 50% aqueous solution of diethylamine isthen added to the reaction mixture. The reaction mixture is allowed towarm to room temperature and stirred for about 2 hours. The product isisolated by the addition of excess water followed by ether extraction ofthe organic phase with successively, 1 N hydrochloric acid and 5% sodiumbicarbonate solution, followed by drying over sodium sulfate.

                                      TABLE                                       __________________________________________________________________________    1-R.sub.1 -1-cyclopentene-cis-3,5 diols (1)                                   R.sub.1 Z        % Yield, 1                                                                           Mp (bp) ° C                                                                     Formula                                                                             %C; %H Cal.sub.c.                                                                     %C: %H found                   __________________________________________________________________________    1(CH.sub.2).sub.5 CH.sub.3                                                                     50-60  75 (5.10.sup. -3 mm)                                                                   C.sub.11 M.sub.20 O.sub.2                                                           71.69; 10.94                                                                          71.33; 10.78                    ##STR13##       54     51-52.5  C.sub.14 H.sub.24 O.sub.4                                                           65.60; 9.94                                                                           65.76; 9.33                    1(CH.sub.2).sub.5 CO.sub.2 tBu                                                                 45     110 (.01 mm)                                                                           C.sub.16 H.sub.28 O.sub.4                                                           67.57; 9.93                                                                           67.59; 9.77                    BrCH.sub.2 CC(CH.sub.2).sub.3 CO.sub.2 t-Bu                                                    33     60 (5.10.sup.-3 mm)                                                                    C.sub.16 H.sub.24 O.sub.4                                                           68.55; 8.63                                                                           68.39; 8.79                    BrCH.sub.2 C.sub.6 H.sub.5                                                                     50     95-96.5  C.sub.12 H.sub.14 O.sub.2                                                           75.76; 7.42                                                                           75.56; 7.41                    BrCH.sub.2 CHCHC.sub.6 H.sub.5                                                                 64     103-105  C.sub.14 H.sub.16 O.sub.2                                                           77.75; 7.46                                                                           77.64; 7.57                    __________________________________________________________________________

the representative cis-diols 1 listed in the Table can be purified bychromatography on neutral alumina (Activity lll). The cis-diolsstereochemistry in 1 is readily assigned by an examination of the 'H-nmrchemical shifts and splitting patterns of the C-4 methylene protons.Thus in 2 (R₁ = CH₂ C₆ H₅) the 'H-nmr chemical shifts of the C-4 protons(CDCl₃) are 2.60δ (5-line multiplet) and 1.58δ (triplet or doublets).The corresponding protons in 8 appear at 2.66 and 1.51δ. Reference ismade in this respect to F. G. Cocu, G. Woiczunowics, L. Bors, T.Posternak, Helv. Chem. Acta, 53, 739 (1970).

Compound 1 can be transformed into prostaglandin precursor 2 by thefollowing route. The oxidation of 1 to the dione 13 is carried out witha variety of reagents such as ##STR14## Jones reagent (85% yield). Thecharacteristic ir spectra (neat) of these compounds exhibit a broadcarbonyl frequency at 1705 cm⁻¹ and in the nmr spectra, a vinyl'H-resonance at 7.83 δ (CCl₄).

Selective protection of the ene-dione can be accomplished in thefollowing way. Treatment of 13 with trimethylsilyl cyanide in a varietyof nonhydroxylic solvents such as benzene or ether in the presence of acatalytic amount of triphenylphosphine or cyanide ion cleanly affords14. These compounds are rather difficult to handle and for that reasonwere not fully characterized. The diagnostic nmr spectra (CCl₄) of thesederivatives exhibit vinyl hydrogen absorption at 5.95 δ (1H) and aquartet centered at 2.7 δ (J=18Hz). Compound 14 can be selectivelyreduced with reducing reagents such as lithium aluminum hydride orsodium porphydride followed by reconstruction of the keto group such asby hydrolysis with aqueous silver fluoride. The method of transforming13 to 14 follows the method disclosed in J. Amer. Chem. Soc., 95 5822(1973) and Chem. Commun. 55 (1973). The transformation ofhydroxyl-protected derivatives of 2 to prostaglandins and prostaglandinanalogs of the E-type is completed according to procedures described inthe literature, for example E. J. Corey, D. J. Beames, J. Amer. Chem.Soc., 94, 7210 (1972); F. S. Alverez, D. Wren, A. Price, ibid., 94, 7823(1972); A. F. Kluge, K. G. Untch, J. H. Fried, ibid., 94, 7827 (1972);C. H. Sih, J. B. Heather, G. P. Peruzzotti, P. Price, R. Sood, L. H.Lee, ibid., 95, 1676 (1973) and cited references.

The derivatives 2 possessing the terminal 1,3-dioxacyclopentyl group canbe transformed into the corresponding carboxyl compounds by knownmethods, after protecting hydroxyl group. The resulting carboxylterminated compounds can then be transformed into prostaglandins asabove noted.

A second use of intermediate 1 in prostaglandin synthesis is shownschematically below. Compound species of 1 (below) can be oxidized withreagents such as: ##STR15## where R₄ and R₅ are each hydrogen, alkyl oraryl groups preferably hydrogen, alkyl of from 1 to 12 carbons and arylof from 6 to 12 carbon atoms such as methyl, ethyl, propyl, phenyl andthe like with ozone to the lactol 16 which can be protected with twoequivalents of trimethylsilyl methyl sulfide in solvents such asacetonitrile to give compound 17 (Y=SCH₃). Intermediate 17 and similarderivatives such as those where Y=SR₂ or OR₂ where R₂ is a hydrocarbonradical of from 1 to 9 carbons such as alkyl are useful intermediates inprostaglandin synthesis. For example, employing standard organoboronchemistry 17 can be transformed to either 18 or 19 by the sequence ofreactions illustrated below. The important concept here involves thehydroboration and subsequent transformation of ##STR16## compound 17 toeither 18 or 19 by the steps shown above wherein R₄ is as defined above.

The reaction 17 - 18 follows that as described in J. Amer. Chem. Soc. 923503. Thus the borane and (17) can be reacted and the reaction productthen reacted with the acylacetylene during aeration.

The reaction 17 - 19 can be carried out in accordance with thedisclosure of Accounts Chem. Res. 2, 65. Thus 17 (R=C_(e) H₅) can behydroborated in the usual manner at atmospheric pressure and thensubjected to gaseous carbon monoxide under agitation as long asabsorption continues.

The transformation of both 18 and 19 to F-prostaglandins is disclosed inJ. Amer. Chem. Soc. 93, 1491.

I claim:
 1. A compound selected from the group consisting of ##STR17##where R is phenyl or alkyl of from 1 to 12 carbon atoms.